Diseases with a genetic basis are usually diagnosed by looking for causal mutations in a panel of genes specifically associated with the disease. Gathering all phenotypes associated with the genes in a panel delivers a general phenotype-level description beyond the disease under study. For the purpose of improving genetic diagnosis, we need methods to evaluate the gene level phenotypic similarity between diseases and to identify differential phenotypes between the gene sets associated. Comparative phenotypic similarity analysis between gene panels can demonstrate common pathophysiology and help to create genetic links between diseases through their gene sets. PhenoExam works on this principle by integrating databases like The Human Phenotype Ontology (HPO) and The Mouse Genome Database (MGD).
PhenoExamWeb is an R package that performs (1) phenotype enrichment analysis on a gene set, (2) measures statistically significant phenotype similarities between gene sets and (3) detects significant differential phenotypes for them. Phenotypic Similarity between two groups of genes is performed by assessing the statistical significance of the Phenotypic Overlap Ratio (POR) between those (i.e. the number of common phenotypes between the gene sets). PhenoExamWeb uses the HPO, MGD, and CRISPRbrain databases.
In this tutorial, we applied PhenoExamWeb to the detection of differential phenotypes between gene sets by comparing two genetic diseases with similar symptoms: juvenile Parkinson disease (PD) with 35 genes and early onset dystonia (EOD) with 50 genes from Genomics England PanelApp.
First, we are going to do a phenotype enrichment analysis with PhenoExamWeb in Parkinson gene set.
It is interesting to determine which are the significant phenotypes in a given set of gene G. In order to calculate whether a gene set G shows enrichment in a given phenotypic term p, we calculate the number of genes g in a gene set G associated with the phenotypic term p, on the other hand, we calculate the number of genes in the reference database gdb associated with that phenotypic term p. The total universe of genes in the database GDB and the number of genes in the given set of genes G are taken into account. With this data we use a hypergeometric distribution. Where the population size is GDB, G is the size of the sample drawn, gdb is the number of items in the original population that belong to the desired category (to phenotype p in our case) and g is the number of items in the sample that belong to that category. Any phenotype with p < 0.05 will be enriched in the G gene set. We compute this for each phenotypic term p in a gene set G.
We select the juvenile Parkinson disease (PD) gene set with 35 genes from Genomics England PanelApp (G2PML package) We show the Phenotype Enrichment Analysis for Parkinson Disease genes from GenomicEngland made in all databases with PhenoExamWeb (HPO, MGD and CRISPRBrain):
# Get the panels
paneles <- getPanelsFromPanelApp()
# Get PD panel
parkinsonpanel<- getPanelFromPanelApp(disorder = "Neurology and neurodevelopmental disorders" , panel = "Parkinson Disease and Complex Parkinsonism")
parkinsonpanelf <- filter(parkinsonpanel, parkinsonpanel$LevelOfConfidence == "HighEvidence")
# Get PD high evidence genes (note that is a vector)
parkinsongenes <- parkinsonpanelf$GeneSymbol
# Get dystonia panel
dystonia <- getPanelFromPanelApp(disorder = "Neurology and neurodevelopmental disorders" , panel = "Early onset dystonia")
dystoniapanel <- filter(dystonia, dystonia$LevelOfConfidence == "HighEvidence")
# Ges dystonia genes
dystoniagenes <- dystoniapanel$GeneSymbolIt is important have the genes in a vector.
Now we can use PhenoEnrichGenes function:
parkinsonenrich <- PhenoEnrichGenes(genes= parkinsongenes, database = "ALL", plotn = 25) # For all database at the same time
parkinsonenrichmp <- PhenoEnrichGenes(genes= parkinsongenes, database = "MGD", plotn = 25) # For MGD
parkinsonenrichcrb <- PhenoEnrichGenes(genes= parkinsongenes, database = "CRB", plotn = 25) # For CRBWe observe in this table the 20 most enriched phenotypic terms:
kbl(parkinsonenrich$htmltabla[1:20,], escape = F, digits = 1000, align = "c", format = "html", row.names = F) %>%
kable_material_dark() | term_id | term_name | adjust_pvalue | genes_associated_in_db | gene_overlap | overlap_ratio | pvalue | common_genes |
|---|---|---|---|---|---|---|---|
| HP:0002067 | Bradykinesia | 1.870582e-60 | 97 | 29 | (29/97) | 3.081683e-63 | PLA2G6, PRKRA, ATP1A3, SYNJ1, LYST, FBXO7, CSF1R, DNAJC6, DCTN1, C19ORF12, RAB39B, FTL, GBA, GCH1, WDR45, PARK7, MAPT, PRKN, LRRK2, PANK2, SLC30A10, SLC6A3, VPS35, SNCA, SPR, ATP13A2, TH, SLC39A14, PINK1 |
| HP:0001300 | Parkinsonism | 2.297659e-51 | 98 | 26 | (26/98) | 3.785269e-54 | PLA2G6, PRKRA, ATP1A3, SYNJ1, FBXO7, DNAJC6, DCTN1, C19ORF12, RAB39B, FTL, GBA, GCH1, GRN, WDR45, MAPT, PRKN, PANK2, SLC30A10, SLC6A3, VPS35, SNCA, VPS13A, ATP13A2, TH, SLC39A14, PINK1 |
| HP:0002063 | Rigidity | 1.628465e-46 | 144 | 26 | (26/144) | 2.682809e-49 | PLA2G6, SYNJ1, LYST, FBXO7, CSF1R, DNAJC6, DCTN1, C19ORF12, TUBB4A, FTL, GBA, GCH1, WDR45, PARK7, MAPT, PRKN, LRRK2, PANK2, SLC30A10, SLC6A3, VPS35, SNCA, SPR, ATP13A2, TH, PINK1 |
| HP:0001337 | Tremor | 7.767941e-41 | 343 | 28 | (28/343) | 1.279727e-43 | PLA2G6, SYNJ1, LYST, FBXO7, DNAJC6, DCTN1, C19ORF12, TUBB4A, FTL, GBA, GCH1, WDR45, PARK7, MAPT, PRKN, LRRK2, PANK2, SLC30A10, OPA3, SPG11, SLC6A3, SNCA, SPR, VPS13A, ATP13A2, TH, SLC39A14, PINK1 |
| C0752105 | Parkinsonism, Juvenile | 3.339899e-33 | 30 | 15 | (15/30) | 2.402805e-35 | ATP1A3, DCTN1, GBA, MAPT, PRKN, SNCA, TH, PRKRA, SYNJ1, PARK7, ATP13A2, FBXO7, SLC30A10, PINK1, LRRK2 |
| HP:0002172 | Postural instability | 3.665796e-32 | 59 | 17 | (17/59) | 6.039203e-35 | PLA2G6, ATP1A3, SYNJ1, FBXO7, CSF1R, DNAJC6, C19ORF12, GBA, PARK7, MAPT, PRKN, LRRK2, SLC30A10, VPS35, SNCA, ATP13A2, PINK1 |
| HP:0000338 | Hypomimic face | 7.629024e-32 | 32 | 15 | (15/32) | 1.256841e-34 | PLA2G6, ATP1A3, SYNJ1, FBXO7, DNAJC6, FTL, GBA, LRRK2, SLC30A10, SLC6A3, VPS35, SNCA, SPR, ATP13A2, SLC39A14 |
| HP:0001332 | Dystonia | 1.946153e-30 | 323 | 23 | (23/323) | 3.206184e-33 | PLA2G6, ATP1A3, SYNJ1, FBXO7, DNAJC6, C19ORF12, TUBB4A, FTL, GBA, GCH1, WDR45, PARK7, MAPT, PRKN, LRRK2, PANK2, SLC30A10, VPS35, SNCA, SPR, VPS13A, ATP13A2, PINK1 |
| C0242423 | Ramsay Hunt Paralysis Syndrome | 6.798872e-28 | 28 | 13 | (13/28) | 4.891275e-30 | ATP1A3, DCTN1, GBA, MAPT, PRKN, SNCA, TH, PRKRA, PARK7, ATP13A2, SLC30A10, PINK1, LRRK2 |
| C0752097 | Autosomal Dominant Juvenile Parkinson Disease | 6.798872e-28 | 28 | 13 | (13/28) | 4.891275e-30 | ATP1A3, DCTN1, GBA, MAPT, PRKN, SNCA, TH, PRKRA, PARK7, ATP13A2, SLC30A10, PINK1, LRRK2 |
| C0752098 | Autosomal Dominant Parkinsonism | 6.798872e-28 | 28 | 13 | (13/28) | 4.891275e-30 | ATP1A3, DCTN1, GBA, MAPT, PRKN, SNCA, TH, PRKRA, PARK7, ATP13A2, SLC30A10, PINK1, LRRK2 |
| C0752100 | Autosomal Recessive Parkinsonism | 6.798872e-28 | 28 | 13 | (13/28) | 4.891275e-30 | ATP1A3, DCTN1, GBA, MAPT, PRKN, SNCA, TH, PRKRA, PARK7, ATP13A2, SLC30A10, PINK1, LRRK2 |
| C0752101 | Parkinsonism, Experimental | 6.798872e-28 | 28 | 13 | (13/28) | 4.891275e-30 | ATP1A3, DCTN1, GBA, MAPT, PRKN, SNCA, TH, PRKRA, PARK7, ATP13A2, SLC30A10, PINK1, LRRK2 |
| C0752104 | Familial Juvenile Parkinsonism | 6.798872e-28 | 28 | 13 | (13/28) | 4.891275e-30 | ATP1A3, DCTN1, GBA, MAPT, PRKN, SNCA, TH, PRKRA, PARK7, ATP13A2, SLC30A10, PINK1, LRRK2 |
| C1868675 | PARKINSON DISEASE 2, AUTOSOMAL RECESSIVE JUVENILE | 6.798872e-28 | 28 | 13 | (13/28) | 4.891275e-30 | ATP1A3, DCTN1, GBA, MAPT, PRKN, SNCA, TH, PRKRA, PARK7, ATP13A2, SLC30A10, PINK1, LRRK2 |
| HP:0001347 | Hyperreflexia | 4.463175e-25 | 554 | 23 | (23/554) | 7.352842e-28 | PLA2G6, PRKRA, SYNJ1, FBXO7, CSF1R, DNAJC6, DCTN1, C19ORF12, FTL, GBA, GCH1, GRN, PARK7, MAPT, PRKN, LRRK2, PANK2, OPA3, SPG11, SNCA, SPR, ATP13A2, PINK1 |
| HP:0001260 | Dysarthria | 4.925506e-25 | 459 | 22 | (22/459) | 8.114507e-28 | PLA2G6, PRKRA, ATP1A3, SYNJ1, FBXO7, CSF1R, DNAJC6, DCTN1, C19ORF12, RAB39B, TUBB4A, FTL, GBA, MAPT, PANK2, SLC30A10, OPA3, SPG11, SNCA, SPR, VPS13A, ATP13A2 |
| HP:0000726 | Dementia | 1.215767e-24 | 150 | 17 | (17/150) | 2.002911e-27 | FBXO7, DCTN1, C19ORF12, RAB39B, TUBB4A, FTL, GBA, GRN, WDR45, MAPT, LRRK2, PANK2, VPS35, SNCA, VPS13A, ATP13A2, PINK1 |
| HP:0002548 | Parkinsonism with favorable response to dopaminergic medication | 5.590449e-24 | 19 | 11 | (11/19) | 9.209965e-27 | PLA2G6, FBXO7, GBA, GCH1, PARK7, MAPT, LRRK2, VPS35, SNCA, ATP13A2, TH |
| HP:0000741 | Apathy | 2.025854e-23 | 48 | 13 | (13/48) | 3.337485e-26 | SYNJ1, DNAJC6, DCTN1, GBA, GRN, PARK7, MAPT, PRKN, LRRK2, VPS35, SNCA, ATP13A2, PINK1 |
We get a plot with the 25 most enriched phenotypic terms. For example, we observe some interesting phenotypes such as Bradykinesia, Parkinsonism, Tremor and Lewy bodies.
We can obtain the same plot for CRB terms, in this case we don’t have any enrichment phenotype but we can see the genes associated with these phenotypes. For example, we can see the association with reactive oxygen species in glutamatergic neuron in these genes (ATP1A3, FBXO7, MAPT, OPA3, VPS35 and WDR45).
We can get the same plot for MP terms. For example, we observe some interesting phenotypes such as abnormal gait, neuron degeneration, astrocytosis, loss of dopaminergic neuron and lipofuscinosis.
We use RandomComparePheno function.
PhenoExam can compare the phenotype analysis of two gene sets in order to determine the similarity of phenotypes and find the phenotypic differences that make each gene set unique. In this case we are going to compare Parkinson genes with Dystonia genes.
comparareparkdis <- RandomComparePheno(parkinsongenes,dystoniagenes,database = "ALL", nulltestnumber = 1000)First, we get a message with the summary of the analysis:
## [1] "Gene set2 and gene set1 shared 1104 phenotypic terms (out of 2336 unique phenotypic terms in both), that yields a Relaxed Phenotypic Overlap Ratio (RPOR) of 0.473 (p < 0.000999). They shared 140 significant phenotypic terms (out of 267 unique significant phenotypic terms in both), that yields a Phenotypic Overlap Ratio (POR) of 0.524 (p < 0.000999). Phenotype relevance association analysis for gene sets (i.e. whether the shared phenotypes are similar in relevance, i.e. in the number of genes associated with them, within each gene set) results in an adjusted R squared of 0.665 ( p < 0) which suggests that an important portion of the common phenotypes are similar in relevance. The p-values were obtained through randomization of 1000 random gene sets. Gene set 1 and gene set 2 are statistically significantly similar to each other in phenotypic terms."
Once the enrichment phenotypes of a gene set have been determined (i.e phenotypes with p < 0.05 in each gene set), it may be useful to calculate the number of these phenotypes shared between two gene sets (G and G’) to know what ratio of phenotypic terms those gene sets share.
In addition to calculating which enrichment phenotypes share two gene sets, we will be interested in determining whether this is due to the random chance. We can determine whether the Phenotypic Overlap Ratio (POR) is statistically significant by using randomization. To answer the question of whether the phenotypic overlap between G and G’ is significant. i.e. for G and G’, POR (G,G’) is compared with the POR of a random gene set POR (G,R) and POR (G’,R), where R has the same number of genes as G’ or G respectively, all genes are selected at random and all are protein coding. We can calculate the POR for different random gene sets (R1,R2,…,Rm). We can now check how many random gene sets have a higher POR than our test, if the number of higher POR of these random gene sets is less than 5% of the total then p < 0.05 and we could conclude that the number of phenotypes shared between these two gene sets is statistically significant.
Parkinson genes and Dystonia genes get a Phenotypic Overlap Ratio (POR) of 0.524 (p < 0.00999). We get a plot with the 1000 randomization values of the POR score:
Not this time but sometimes POR is too demanding and valuable information cannot be obtained. In these cases it is useful Relaxed Phenotypic Overlap Ratio (RPOR). RPOR is calculated in a similar way to the POR but with all phenotypes, whether these are enriched or not.
Parkinson genes and Dystonia genes get a Relaxed Phenotypic Overlap Ratio (RPOR) of 0.473 (p < 0.00999). We get a plot with the 1000 randomization values of the RPOR score:
We can measure the linear regression with the adjusted R square and if it is significant with the pvalue of the regression. If there is no linear relationship there is no consistent pattern of association of phenotypic relevance.
Besides measuring the phenotypic similarities between the two gene sets we can also see in which phenotypes are not similar, that is, which phenotypes make that gene set unique with respect to the other.
We get an interactive plot with the relevant phenotypic terms for each gene set:
For example, significant only in PD phenotypes include Astrocytosis (MP:0003354), Substantia nigra gliosis (HP:0011960), Neuronal loss in central nervous system (HP:0002529) and Orthostatic hypotension due to autonomic dysfunction (HP:0004926).
kbl(comparareparkdis$tabledif1, escape = F, digits = 1000, align = "c", format = "html", row.names = F) %>%
kable_material_dark()| term_id | term_name | adjust_pvalue_set1 | gene_overlap_set1 | overlap_ratio_set1 | pvalue_set1 | common_genes_set1 | adjust_pvalue_set2 | gene_overlap_set2 | overlap_ratio_set2 | pvalue_set2 | common_genes_set2 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| MP:0003354 | astrocytosis | 4.696161e-12 | 11 | (11/159) | 6.059562e-15 | ATP13A2, ATP1A3, DCTN1, GBA, GRN, LRRK2, MAPT, SNCA, SPG11, TUBB4A, WDR45 | 0.06876015 | 5 | (5/159) | 8.426488e-05 | ATP13A2, ATP1A3, TUBB4A, VAC14, WDR45 |
| HP:0011960 | Substantia nigra gliosis | 4.131233e-11 | 6 | (6/14) | 6.805985e-14 | FBXO7, GBA, MAPT, PRKN, LRRK2, SNCA | 0.47496849 | 2 | (2/14) | 6.128626e-04 | FBXO7, PRKN |
| HP:0002171 | Gliosis | 2.599204e-10 | 8 | (8/70) | 4.282049e-13 | PLA2G6, CSF1R, GBA, GRN, MAPT, LRRK2, VPS35, SNCA | 1.00000000 | 2 | (2/70) | 1.471849e-02 | PLA2G6, YY1 |
| HP:0002367 | Visual hallucinations | 3.702765e-10 | 6 | (6/19) | 6.100108e-13 | FBXO7, GBA, LRRK2, VPS35, SNCA, ATP13A2 | 0.88454551 | 2 | (2/19) | 1.141349e-03 | FBXO7, ATP13A2 |
| MP:0008918 | microgliosis | 2.179921e-09 | 8 | (8/82) | 2.812801e-12 | ATP1A3, CSF1R, DCTN1, GRN, LRRK2, MAPT, SLC6A3, VPS35 | 1.00000000 | 2 | (2/82) | 2.268157e-02 | ATP1A3, SLC6A3 |
| HP:0003677 | Slow progression | 6.957523e-09 | 9 | (9/166) | 1.146215e-11 | FBXO7, DNAJC6, DCTN1, C19ORF12, PARK7, LRRK2, PANK2, SPG11, PINK1 | 0.05700405 | 5 | (5/166) | 7.355361e-05 | FBXO7, C19ORF12, HPCA, PANK2, PINK1 |
| HP:0007311 | Short stepped shuffling gait | 3.840002e-08 | 5 | (5/16) | 6.326198e-11 | SYNJ1, DNAJC6, DCTN1, GBA, MAPT | 1.00000000 | 1 | (1/16) | 4.154390e-02 | SYNJ1 |
| HP:0001621 | Weak voice | 1.354524e-07 | 5 | (5/20) | 2.231506e-10 | SYNJ1, DNAJC6, DCTN1, GBA, MAPT | 1.00000000 | 1 | (1/20) | 5.165212e-02 | SYNJ1 |
| HP:0002359 | Frequent falls | 1.600395e-07 | 7 | (7/92) | 2.636565e-10 | C19ORF12, GBA, MAPT, LRRK2, PANK2, VPS35, SNCA | 0.07826672 | 4 | (4/92) | 1.009893e-04 | ADAR, C19ORF12, FA2H, PANK2 |
| HP:0002366 | Abnormal lower motor neuron morphology | 2.926082e-07 | 5 | (5/23) | 4.820563e-10 | DCTN1, C19ORF12, GRN, MAPT, SPG11 | 1.00000000 | 2 | (2/23) | 1.676591e-03 | CHMP2B, C19ORF12 |
| MP:0001262 | decreased body weight | 8.789076e-07 | 17 | (17/1739) | 1.134074e-09 | ATP1A3, CSF1R, DNAJC6, GBA, GRN, MAPT, OPA3, PANK2, PINK1, PRKN, PRKRA, SLC30A10, SLC39A14, SLC6A3, SNCA, SPR, TH | 0.07926118 | 14 | (14/1739) | 9.713380e-05 | ATM, ATP1A3, ATP7B, GNAO1, HTRA2, PANK2, PINK1, PRKN, PRKRA, SLC30A10, SLC6A3, SPR, TH, TOR1A |
| HP:0005340 | Spastic/hyperactive bladder | 1.155982e-06 | 4 | (4/10) | 1.904418e-09 | GBA, LRRK2, VPS35, SNCA | 1.00000000 | 0 | 1 | 1.000000e+00 | 1 |
| HP:0003581 | Adult onset | 1.913557e-06 | 7 | (7/131) | 3.152483e-09 | CSF1R, DCTN1, GBA, PARK7, MAPT, PRKN, SPG11 | 0.30200968 | 4 | (4/131) | 3.896899e-04 | CP, CHMP2B, PRKN, APTX |
| C0497327 | Dementia | 2.694854e-06 | 4 | (4/17) | 1.938744e-08 | CSF1R, GRN, MAPT, SLC6A3 | 0.23096934 | 2 | (2/17) | 8.683058e-04 | CP, SLC6A3 |
| HP:0000012 | Urinary urgency | 3.708838e-06 | 5 | (5/37) | 6.110113e-09 | GBA, MAPT, SPG11, SNCA, PINK1 | 1.00000000 | 2 | (2/37) | 4.304295e-03 | FA2H, PINK1 |
| HP:0002529 | Neuronal loss in central nervous system | 3.708838e-06 | 5 | (5/37) | 6.110113e-09 | PLA2G6, CSF1R, GBA, GRN, MAPT | 0.09847174 | 3 | (3/37) | 1.270603e-04 | PLA2G6, CHMP2B, VAC14 |
| HP:0031908 | Micrographia | 5.477310e-06 | 4 | (4/14) | 9.023575e-09 | FTL, GBA, MAPT, SNCA | 1.00000000 | 1 | (1/14) | 3.644866e-02 | FTL |
| HP:0002375 | Hypokinesia | 6.336739e-06 | 5 | (5/41) | 1.043944e-08 | GBA, SLC6A3, SNCA, ATP13A2, TH | 0.13401312 | 3 | (3/41) | 1.729202e-04 | SLC6A3, ATP13A2, TH |
| HP:0002120 | Cerebral cortical atrophy | 6.708363e-06 | 8 | (8/249) | 1.105167e-08 | GBA, GRN, LRRK2, SPG11, VPS35, SNCA, VPS13A, ATP13A2 | 0.36796339 | 5 | (5/249) | 4.747915e-04 | CHMP2B, BCAP31, FA2H, VPS13A, ATP13A2 |
| HP:0002300 | Mutism | 7.181883e-06 | 5 | (5/42) | 1.183177e-08 | ATP1A3, CSF1R, FTL, GRN, MAPT | 0.14403143 | 3 | (3/42) | 1.858470e-04 | ATP1A3, CHMP2B, FTL |
| HP:0000744 | Low frustration tolerance | 7.457898e-06 | 4 | (4/15) | 1.228649e-08 | GBA, LRRK2, VPS35, SNCA | 1.00000000 | 0 | 1 | 1.000000e+00 | 1 |
| HP:0004926 | Orthostatic hypotension due to autonomic dysfunction | 9.929007e-06 | 4 | (4/16) | 1.635751e-08 | GBA, LRRK2, VPS35, SNCA | 1.00000000 | 0 | 1 | 1.000000e+00 | 1 |
| MP:0004250 | tau protein deposits | 1.272881e-05 | 4 | (4/15) | 1.642427e-08 | GRN, LRRK2, MAPT, PRKN | 1.00000000 | 1 | (1/15) | 4.188862e-02 | PRKN |
| MP:0002882 | abnormal neuron morphology | 1.733258e-05 | 7 | (7/162) | 2.236462e-08 | ATP13A2, GBA, LRRK2, MAPT, PRKN, SLC6A3, SPG11 | 0.07504847 | 5 | (5/162) | 9.197116e-05 | ATP13A2, CP, PRKN, SLC6A3, TOR1A |
| MP:0005405 | axon degeneration | 2.187874e-05 | 6 | (6/96) | 2.823063e-08 | OPA3, PLA2G6, SNCA, SPG11, TUBB4A, WDR45 | 0.12809691 | 4 | (4/96) | 1.569815e-04 | NKX6-2, PLA2G6, TUBB4A, WDR45 |
| MP:0001473 | reduced long term potentiation | 2.937642e-05 | 7 | (7/175) | 3.790505e-08 | GRN, MAPT, PINK1, SLC6A3, SNCA, VPS35, WDR45 | 1.00000000 | 3 | (3/175) | 1.323181e-02 | PINK1, SLC6A3, WDR45 |
| HP:0002145 | Frontotemporal dementia | 3.240804e-05 | 4 | (4/21) | 5.339051e-08 | PLA2G6, DCTN1, GRN, MAPT | 1.00000000 | 2 | (2/21) | 1.396636e-03 | PLA2G6, CHMP2B |
| HP:0001824 | Weight loss | 4.719093e-05 | 7 | (7/209) | 7.774453e-08 | DCTN1, GBA, LRRK2, PANK2, VPS35, SNCA, VPS13A | 1.00000000 | 4 | (4/209) | 2.178300e-03 | ATM, ATP7B, PANK2, VPS13A |
| HP:0002014 | Diarrhea | 5.714044e-05 | 7 | (7/215) | 9.413581e-08 | SYNJ1, DNAJC6, PARK7, PRKN, LRRK2, SNCA, PINK1 | 0.18907978 | 5 | (5/215) | 2.439739e-04 | SYNJ1, DDC, HTRA2, PRKN, PINK1 |
| HP:0002465 | Poor speech | 5.895907e-05 | 7 | (7/216) | 9.713191e-08 | CSF1R, RAB39B, TUBB4A, GRN, WDR45, MAPT, SLC39A14 | 0.19313478 | 5 | (5/216) | 2.492062e-04 | CHMP2B, DLAT, TUBB4A, WDR45, WDR73 |
| MP:0008842 | lipofuscinosis | 6.744999e-05 | 4 | (4/22) | 8.703225e-08 | ATP13A2, GBA, GRN, LRRK2 | 1.00000000 | 1 | (1/22) | 6.082009e-02 | ATP13A2 |
| HP:0000505 | Visual impairment | 7.869031e-05 | 8 | (8/344) | 1.296381e-07 | PLA2G6, SYNJ1, LYST, CSF1R, TUBB4A, GRN, OPA3, SPG11 | 1.00000000 | 4 | (4/344) | 1.220619e-02 | PLA2G6, SYNJ1, MECR, TUBB4A |
| HP:0000514 | Slow saccadic eye movements | 8.034995e-05 | 4 | (4/26) | 1.323722e-07 | FBXO7, MAPT, SNCA, ATP13A2 | 1.00000000 | 2 | (2/26) | 2.142177e-03 | FBXO7, ATP13A2 |
| MP:0004077 | abnormal striatum morphology | 8.188499e-05 | 5 | (5/60) | 1.056581e-07 | GBA, LRRK2, PARK7, SLC6A3, SNCA | 1.00000000 | 1 | (1/60) | 1.571363e-01 | SLC6A3 |
| MP:0001463 | abnormal spatial learning | 9.175795e-05 | 7 | (7/207) | 1.183974e-07 | ATP13A2, ATP1A3, GRN, MAPT, PRKN, SLC6A3, VPS35 | 0.23290669 | 5 | (5/207) | 2.854249e-04 | ATP13A2, ATP1A3, FA2H, PRKN, SLC6A3 |
| C3160718 | PARKINSON DISEASE, LATE-ONSET | 1.545833e-04 | 3 | (3/12) | 1.112110e-06 | GBA, MAPT, PRKN | 1.00000000 | 1 | (1/12) | 3.058383e-02 | PRKN |
| MP:0010069 | increased serotonin level | 1.869844e-04 | 4 | (4/28) | 2.412702e-07 | PARK7, PRKN, SLC6A3, TH | 0.05518245 | 3 | (3/28) | 6.762555e-05 | PRKN, SLC6A3, TH |
| MP:0001263 | weight loss | 2.326296e-04 | 8 | (8/358) | 3.001672e-07 | LYST, PARK7, PLA2G6, SLC6A3, SNCA, SPG11, TH, TUBB4A | 1.00000000 | 5 | (5/358) | 3.164514e-03 | PLA2G6, SLC6A3, TH, TOR1A, TUBB4A |
| HP:0012450 | Chronic constipation | 2.462922e-04 | 4 | (4/34) | 4.057532e-07 | GBA, LRRK2, VPS35, SNCA | 1.00000000 | 0 | 1 | 1.000000e+00 | 1 |
| MP:0003172 | abnormal lysosome physiology | 3.262962e-04 | 4 | (4/32) | 4.210274e-07 | ATP13A2, LYST, SLC6A3, SPG11 | 1.00000000 | 2 | (2/32) | 3.726748e-03 | ATP13A2, SLC6A3 |
| HP:0000511 | Vertical supranuclear gaze palsy | 3.970762e-04 | 3 | (3/10) | 6.541618e-07 | DCTN1, MAPT, ATP13A2 | 1.00000000 | 1 | (1/10) | 2.617517e-02 | ATP13A2 |
| MP:0003633 | abnormal nervous system physiology | 4.167109e-04 | 6 | (6/158) | 5.376915e-07 | GRN, MAPT, PINK1, SLC6A3, SNCA, TH | 0.06675656 | 5 | (5/158) | 8.180951e-05 | CSTB, GNAO1, PINK1, SLC6A3, TH |
| MP:0005404 | abnormal axon morphology | 8.057796e-04 | 6 | (6/177) | 1.039716e-06 | LRRK2, MAPT, PLA2G6, SLC6A3, SNCA, TUBB4A | 0.11336100 | 5 | (5/177) | 1.389228e-04 | FA2H, PLA2G6, SLC6A3, TUBB4A, XK |
| HP:0000719 | Inappropriate behavior | 9.423931e-04 | 3 | (3/13) | 1.552542e-06 | DCTN1, GRN, MAPT | 1.00000000 | 1 | (1/13) | 3.389069e-02 | CHMP2B |
| HP:0006892 | Frontotemporal cerebral atrophy | 9.423931e-04 | 3 | (3/13) | 1.552542e-06 | PLA2G6, GRN, MAPT | 0.40784816 | 2 | (2/13) | 5.262557e-04 | PLA2G6, CHMP2B |
| HP:0008969 | Leg muscle stiffness | 9.423931e-04 | 3 | (3/13) | 1.552542e-06 | SYNJ1, DNAJC6, ATP13A2 | 0.40784816 | 2 | (2/13) | 5.262557e-04 | SYNJ1, ATP13A2 |
| MP:0001906 | increased dopamine level | 9.994741e-04 | 4 | (4/42) | 1.289644e-06 | PARK7, PRKN, SLC6A3, SNCA | 1.00000000 | 2 | (2/42) | 6.346209e-03 | PRKN, SLC6A3 |
| C0752347 | Lewy Body Disease | 1.067389e-03 | 3 | (3/22) | 7.679058e-06 | GBA, SNCA, TH | 1.00000000 | 1 | (1/22) | 5.534097e-02 | TH |
| MP:0013219 | abnormal substantia nigra pars compacta morphology | 1.495671e-03 | 3 | (3/13) | 1.929898e-06 | PARK7, PRKN, SLC6A3 | 0.49606651 | 2 | (2/13) | 6.079246e-04 | PRKN, SLC6A3 |
| HP:0002186 | Apraxia | 1.887665e-03 | 4 | (4/56) | 3.109826e-06 | PLA2G6, CSF1R, GRN, MAPT | 0.33812626 | 3 | (3/56) | 4.362919e-04 | PLA2G6, CHMP2B, SLC2A1 |
| HP:0002380 | Fasciculations | 2.174027e-03 | 4 | (4/58) | 3.581594e-06 | DCTN1, GRN, MAPT, SPG11 | 1.00000000 | 1 | (1/58) | 1.424249e-01 | CHMP2B |
| MP:0011451 | increased susceptibility to dopaminergic neuron neurotoxicity | 2.372314e-03 | 3 | (3/15) | 3.061051e-06 | GRN, PARK7, SLC6A3 | 1.00000000 | 1 | (1/15) | 4.188862e-02 | SLC6A3 |
| C0751263 | Learning Disturbance | 2.508527e-03 | 3 | (3/29) | 1.804695e-05 | MAPT, PRKN, TH | 0.67518493 | 2 | (2/29) | 2.538289e-03 | PRKN, TH |
| C0751265 | Learning Disabilities | 2.508527e-03 | 3 | (3/29) | 1.804695e-05 | MAPT, PRKN, TH | 0.67518493 | 2 | (2/29) | 2.538289e-03 | PRKN, TH |
| HP:0003587 | Insidious onset | 2.670015e-03 | 3 | (3/18) | 4.398706e-06 | GBA, MAPT, SNCA | 1.00000000 | 0 | 1 | 1.000000e+00 | 1 |
| HP:0100753 | Schizophrenia | 3.433314e-03 | 4 | (4/65) | 5.656201e-06 | GBA, LRRK2, VPS35, SNCA | 1.00000000 | 0 | 1 | 1.000000e+00 | 1 |
| C0005586 | Bipolar Disorder | 3.465428e-03 | 7 | (7/518) | 2.493114e-05 | ATP1A3, GCH1, GRN, SLC6A3, SPR, TH, PLA2G6 | 0.08020531 | 7 | (7/518) | 3.015237e-04 | ATP1A3, DDC, GCH1, SLC6A3, SPR, TH, PLA2G6 |
| MP:0005059 | lysosomal protein accumulation | 3.534768e-03 | 3 | (3/17) | 4.560991e-06 | ATP13A2, DCTN1, LYST | 1.00000000 | 1 | (1/17) | 4.733698e-02 | ATP13A2 |
| MP:0010149 | abnormal synaptic dopamine release | 3.534768e-03 | 3 | (3/17) | 4.560991e-06 | LRRK2, SLC6A3, SNCA | 1.00000000 | 1 | (1/17) | 4.733698e-02 | SLC6A3 |
| HP:0002185 | Neurofibrillary tangles | 4.333617e-03 | 3 | (3/21) | 7.139403e-06 | PLA2G6, GRN, MAPT | 1.00000000 | 1 | (1/21) | 5.416215e-02 | PLA2G6 |
| HP:0000011 | Neurogenic bladder | 5.754420e-03 | 3 | (3/23) | 9.480098e-06 | FBXO7, SNCA, ATP13A2 | 1.00000000 | 2 | (2/23) | 1.676591e-03 | FBXO7, ATP13A2 |
| MP:0000160 | kyphosis | 6.481472e-03 | 6 | (6/255) | 8.363189e-06 | GBA, PINK1, PLA2G6, PRKN, SLC6A3, SNCA | 1.00000000 | 4 | (4/255) | 5.668553e-03 | PINK1, PLA2G6, PRKN, SLC6A3 |
| MP:0010047 | axonal spheroids | 6.872063e-03 | 3 | (3/21) | 8.867178e-06 | CSF1R, PLA2G6, WDR45 | 1.00000000 | 2 | (2/21) | 1.611633e-03 | PLA2G6, WDR45 |
| C0025261 | Memory Disorders | 8.312055e-03 | 3 | (3/43) | 5.979896e-05 | MAPT, PRKN, SLC6A3 | 1.00000000 | 2 | (2/43) | 5.509350e-03 | PRKN, SLC6A3 |
| MP:0003461 | abnormal response to novel object | 8.755837e-03 | 4 | (4/72) | 1.129785e-05 | ATP13A2, ATP1A3, GRN, SLC6A3 | 0.91344756 | 3 | (3/72) | 1.119421e-03 | ATP13A2, ATP1A3, SLC6A3 |
| MP:0000753 | paralysis | 9.761519e-03 | 4 | (4/74) | 1.259551e-05 | ATP1A3, DCTN1, GBA, PRKRA | 0.98858135 | 3 | (3/74) | 1.211497e-03 | ATP1A3, HTRA2, PRKRA |
| HP:0000709 | Psychosis | 1.043788e-02 | 4 | (4/86) | 1.719585e-05 | GRN, MAPT, PANK2, VPS13A | 0.06025076 | 4 | (4/86) | 7.774292e-05 | CHMP2B, PANK2, DCAF17, VPS13A |
| MP:0008260 | abnormal autophagy | 1.084961e-02 | 4 | (4/76) | 1.399949e-05 | LRRK2, PRKN, SLC6A3, SPG11 | 1.00000000 | 2 | (2/76) | 1.968749e-02 | PRKN, SLC6A3 |
| C0011570 | Mental Depression | 1.176826e-02 | 5 | (5/260) | 8.466377e-05 | ATP1A3, GRN, SLC6A3, SNCA, TH | 0.13757837 | 5 | (5/260) | 5.172119e-04 | ADCY5, ATP1A3, SLC6A3, TH, SGCE |
| MP:0011448 | decreased dopaminergic neuron number | 1.181268e-02 | 3 | (3/25) | 1.524216e-05 | PRKN, SLC6A3, SNCA | 1.00000000 | 2 | (2/25) | 2.284651e-03 | PRKN, SLC6A3 |
| MP:0004811 | abnormal neuron physiology | 1.354081e-02 | 5 | (5/169) | 1.747201e-05 | ATP1A3, GRN, PINK1, SLC6A3, SNCA | 1.00000000 | 4 | (4/169) | 1.311801e-03 | ATP1A3, PINK1, SLC6A3, TOR1A |
| MP:0001399 | hyperactivity | 1.399495e-02 | 8 | (8/631) | 1.805800e-05 | ATP1A3, LRRK2, MAPT, PLA2G6, SLC6A3, SNCA, TH, WDR45 | 0.24682723 | 8 | (8/631) | 3.024843e-04 | ATP1A3, CSTB, GNAO1, PLA2G6, SLC6A3, TH, TOR1A, WDR45 |
| HP:0002344 | Progressive neurologic deterioration | 1.444282e-02 | 3 | (3/31) | 2.379378e-05 | SYNJ1, GBA, GCH1 | 1.00000000 | 2 | (2/31) | 3.037653e-03 | SYNJ1, GCH1 |
| HP:0002483 | Bulbar signs | 1.591464e-02 | 3 | (3/32) | 2.621852e-05 | GBA, SPG11, SLC39A14 | 1.00000000 | 1 | (1/32) | 8.132950e-02 | CHMP2B |
| C0011206 | Delirium | 1.894869e-02 | 2 | (2/10) | 1.363215e-04 | SLC6A3, TH | 0.07736782 | 2 | (2/10) | 2.908565e-04 | SLC6A3, TH |
| MP:0009454 | impaired contextual conditioning behavior | 2.403030e-02 | 4 | (4/93) | 3.100684e-05 | ATP1A3, GRN, MAPT, WDR45 | 1.00000000 | 2 | (2/93) | 2.861596e-02 | ATP1A3, WDR45 |
| MP:0004768 | abnormal axonal transport | 2.520749e-02 | 3 | (3/32) | 3.252579e-05 | MAPT, PRKN, SLC6A3 | 1.00000000 | 2 | (2/32) | 3.726748e-03 | PRKN, SLC6A3 |
| MP:0001732 | postnatal growth retardation | 2.554289e-02 | 9 | (9/915) | 3.295856e-05 | CSF1R, MAPT, OPA3, PANK2, PRKRA, SLC39A14, SLC6A3, SPR, SYNJ1 | 0.57656057 | 9 | (9/915) | 7.065693e-04 | ATM, ATP7B, DDC, HTRA2, PANK2, PRKRA, SLC6A3, SPR, SYNJ1 |
| HP:0002354 | Memory impairment | 2.642845e-02 | 4 | (4/109) | 4.353946e-05 | CSF1R, GRN, MAPT, VPS13A | 0.15027673 | 4 | (4/109) | 1.939055e-04 | CP, CHMP2B, PRRT2, VPS13A |
| MP:0008571 | abnormal synaptic bouton morphology | 2.768659e-02 | 3 | (3/33) | 3.572463e-05 | MAPT, PLA2G6, SLC6A3 | 1.00000000 | 2 | (2/33) | 3.959565e-03 | PLA2G6, SLC6A3 |
| C0030569 | Secondary Parkinson Disease | 2.772393e-02 | 2 | (2/12) | 1.994528e-04 | PRKN, ATP13A2 | 0.11307517 | 2 | (2/12) | 4.250946e-04 | PRKN, ATP13A2 |
| C0751414 | Parkinson Disease, Secondary Vascular | 2.772393e-02 | 2 | (2/12) | 1.994528e-04 | PRKN, ATP13A2 | 0.11307517 | 2 | (2/12) | 4.250946e-04 | PRKN, ATP13A2 |
| C0751415 | Atherosclerotic Parkinsonism | 2.772393e-02 | 2 | (2/12) | 1.994528e-04 | PRKN, ATP13A2 | 0.11307517 | 2 | (2/12) | 4.250946e-04 | PRKN, ATP13A2 |
| MP:0002062 | abnormal associative learning | 3.311306e-02 | 3 | (3/35) | 4.272653e-05 | MAPT, SLC6A3, TH | 1.00000000 | 2 | (2/35) | 4.444897e-03 | SLC6A3, TH |
| HP:0010526 | Dysgraphia | 3.377625e-02 | 3 | (3/41) | 5.564456e-05 | GRN, MAPT, VPS13A | 1.00000000 | 2 | (2/41) | 5.261879e-03 | CHMP2B, VPS13A |
| C0036341 | Schizophrenia | 3.448579e-02 | 8 | (8/1026) | 2.480992e-04 | GCH1, GRN, SLC6A3, PLA2G6, VPS35, PINK1, PANK2, LRRK2 | 0.21177909 | 9 | (9/1026) | 7.961620e-04 | ATM, CP, DDC, GCH1, GNAO1, SLC6A3, PLA2G6, PINK1, PANK2 |
| HP:0000666 | Horizontal nystagmus | 3.632367e-02 | 3 | (3/42) | 5.984130e-05 | GBA, GCH1, ATP13A2 | 0.14403143 | 3 | (3/42) | 1.858470e-04 | GCH1, FA2H, ATP13A2 |
| HP:0002518 | Abnormality of the periventricular white matter | 3.899347e-02 | 3 | (3/43) | 6.423966e-05 | CSF1R, SPG11, ATP13A2 | 1.00000000 | 2 | (2/43) | 5.773851e-03 | FA2H, ATP13A2 |
| C0013386 | Dyskinesia, Drug-Induced | 4.394579e-02 | 2 | (2/15) | 3.161568e-04 | GCH1, TH | 0.17894818 | 2 | (2/15) | 6.727375e-04 | GCH1, TH |
On the other hand, we found significant only phenotypes in EOD such as Writer’s cramp (HP:0002356), Hypoplasia of the corpus callosum (HP:0002079), Acanthocytosis (HP:0001927), Microcephaly (HP:0000252), Intellectual disability, mild (HP:0001256) and Hyperactive deep tendon reflexes (HP:0006801).
kbl(comparareparkdis$tabledif2, escape = F, digits = 1000, align = "c", format = "html", row.names = F) %>%
kable_material_dark()| term_id | term_name | adjust_pvalue_set1 | gene_overlap_set1 | overlap_ratio_set1 | pvalue_set1 | common_genes_set1 | adjust_pvalue_set2 | gene_overlap_set2 | overlap_ratio_set2 | pvalue_set2 | common_genes_set2 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| HP:0002356 | Writer’s cramp | 0.22988089 | 2 | (2/16) | 3.787165e-04 | FTL, GCH1 | 1.544582e-09 | 6 | (6/16) | 1.993010e-12 | SGCE, TOR1A, FTL, GCH1, PRRT2, THAP1 |
| HP:0002355 | Difficulty walking | 0.47371937 | 4 | (4/233) | 7.804273e-04 | SYNJ1, C19ORF12, SLC30A10, ATP13A2 | 1.371032e-08 | 11 | (11/233) | 1.769073e-11 | ADAR, ADCY5, ATP7B, SYNJ1, C19ORF12, NKX6-2, HPCA, FA2H, SLC30A10, COASY, ATP13A2 |
| HP:0003593 | Infantile onset | 0.07185941 | 6 | (6/444) | 1.183845e-04 | PLA2G6, GCH1, SLC6A3, SPR, TH, PINK1 | 5.538158e-08 | 13 | (13/444) | 7.146011e-11 | ADAR, PLA2G6, PNKD, DDC, DLAT, NKX6-2, GCH1, WDR73, SLC2A1, SLC6A3, SPR, TH, PINK1 |
| HP:0003829 | Incomplete penetrance | 1.00000000 | 2 | (2/147) | 2.883347e-02 | ATP1A3, LRRK2 | 3.368622e-06 | 8 | (8/147) | 4.346610e-09 | ATP1A3, SGCE, KMT2B, TOR1A, PRRT2, THAP1, SLC2A1, ANO3 |
| HP:0002487 | Hyperkinetic movements | 0.61490335 | 2 | (2/26) | 1.013020e-03 | GCH1, SLC6A3 | 5.184152e-06 | 5 | (5/26) | 6.689229e-09 | PNKD, GCH1, GNAO1, PRRT2, SLC6A3 |
| HP:0000722 | Obsessive-compulsive behavior | 1.00000000 | 2 | (2/61) | 5.462303e-03 | GCH1, PANK2 | 9.652139e-06 | 6 | (6/61) | 1.245437e-08 | SGCE, TOR1A, GCH1, PANK2, COASY, XK |
| HP:0002079 | Hypoplasia of the corpus callosum | 1.00000000 | 3 | (3/385) | 3.081831e-02 | SYNJ1, SPG11, ATP13A2 | 3.621692e-05 | 10 | (10/385) | 4.673150e-08 | ADAR, SYNJ1, NKX6-2, GNAO1, HTRA2, WDR73, FA2H, COASY, ATP13A2, YY1 |
| HP:0002059 | Cerebral atrophy | 0.11466134 | 5 | (5/302) | 1.888984e-04 | PLA2G6, SYNJ1, GBA, WDR45, SLC39A14 | 5.935410e-05 | 9 | (9/302) | 7.658594e-08 | PLA2G6, SYNJ1, BCAP31, NKX6-2, GNAO1, HTRA2, WDR45, WDR73, SLC2A1 |
| HP:0001270 | Motor delay | 0.05402004 | 6 | (6/421) | 8.899512e-05 | PRKRA, ATP1A3, TUBB4A, GBA, SPR, TH | 8.206003e-05 | 10 | (10/421) | 1.058839e-07 | ADCY5, PRKRA, ATP1A3, KMT2B, MECR, TUBB4A, NKX6-2, WDR73, SPR, TH |
| HP:0000252 | Microcephaly | 1.00000000 | 5 | (5/939) | 2.195749e-02 | SYNJ1, TUBB4A, GBA, SLC30A10, SPR | 3.127271e-04 | 13 | (13/939) | 4.035188e-07 | ADAR, SYNJ1, KMT2B, DLAT, BCAP31, TUBB4A, GNAO1, WDR73, SERAC1, SLC30A10, SLC2A1, COASY, SPR |
| MP:0002183 | gliosis | 0.05681233 | 4 | (4/116) | 7.330623e-05 | ATP13A2, SNCA, TH, VPS13A | 7.270068e-04 | 6 | (6/116) | 8.909397e-07 | ATP13A2, HTRA2, TH, TOR1A, VAC14, VPS13A |
| C0041696 | Unipolar Depression | 0.17968390 | 4 | (4/274) | 1.292690e-03 | FTL, GCH1, TH, PINK1 | 1.545696e-03 | 7 | (7/274) | 5.810888e-06 | ADCY5, ATP7B, DDC, FTL, GCH1, TH, PINK1 |
| HP:0011968 | Feeding difficulties | 0.08093255 | 6 | (6/454) | 1.333320e-04 | PLA2G6, SYNJ1, GBA, SLC6A3, VPS13A, TH | 1.690898e-03 | 9 | (9/454) | 2.181804e-06 | PLA2G6, SYNJ1, WDR73, SERAC1, HPCA, SLC6A3, VPS13A, TH, YY1 |
| MP:0003908 | decreased stereotypic behavior | 0.12819361 | 2 | (2/10) | 1.654111e-04 | PINK1, TH | 2.102033e-03 | 3 | (3/10) | 2.576021e-06 | PINK1, SGCE, TH |
| HP:0002307 | Drooling | 0.33657540 | 3 | (3/89) | 5.544900e-04 | ATP1A3, RAB39B, VPS13A | 2.840632e-03 | 5 | (5/89) | 3.665332e-06 | ATP1A3, ATP7B, DLAT, VAC14, VPS13A |
| MP:0002204 | abnormal neurotransmitter level | 0.15647134 | 2 | (2/11) | 2.018985e-04 | SPR, VPS13A | 2.884006e-03 | 3 | (3/11) | 3.534321e-06 | DDC, SPR, VPS13A |
| HP:0001927 | Acanthocytosis | 0.12706553 | 2 | (2/12) | 2.093337e-04 | PANK2, VPS13A | 2.932568e-03 | 3 | (3/12) | 3.783958e-06 | PANK2, VPS13A, XK |
| HP:0003621 | Juvenile onset | 1.00000000 | 2 | (2/94) | 1.252821e-02 | PANK2, SPG11 | 3.714853e-03 | 5 | (5/94) | 4.793359e-06 | ADCY5, SGCE, HPCA, APTX, PANK2 |
| HP:0045084 | Limb myoclonus | 1.00000000 | 1 | (1/14) | 2.514880e-02 | MAPT | 4.832461e-03 | 3 | (3/14) | 6.235433e-06 | SGCE, TOR1A, SLC2A1 |
| HP:0012075 | Personality disorder | 1.00000000 | 0 | 1 | 1.000000e+00 | 1 | 4.832461e-03 | 3 | (3/14) | 6.235433e-06 | SGCE, TOR1A, XK |
| HP:0001256 | Intellectual disability, mild | 1.00000000 | 1 | (1/271) | 3.872335e-01 | TH | 4.900096e-03 | 7 | (7/271) | 6.322705e-06 | ADAR, DLAT, PRRT2, DCAF17, SLC2A1, TH, YY1 |
| HP:0002061 | Lower limb spasticity | 1.00000000 | 2 | (2/48) | 3.421411e-03 | FBXO7, SPG11 | 5.989559e-03 | 4 | (4/48) | 7.728464e-06 | FBXO7, FA2H, PRRT2, SLC2A1 |
| HP:0002078 | Truncal ataxia | 1.00000000 | 2 | (2/48) | 3.421411e-03 | ATP1A3, SLC30A10 | 5.989559e-03 | 4 | (4/48) | 7.728464e-06 | ATP1A3, NKX6-2, APTX, SLC30A10 |
| HP:0025401 | Staring gaze | 1.00000000 | 1 | (1/15) | 2.692006e-02 | SYNJ1 | 6.028363e-03 | 3 | (3/15) | 7.778533e-06 | SYNJ1, PNKD, PRRT2 |
| HP:0000486 | Strabismus | 1.00000000 | 5 | (5/696) | 6.955770e-03 | PLA2G6, LYST, RAB39B, GBA, ATP13A2 | 6.812392e-03 | 10 | (10/696) | 8.790184e-06 | PLA2G6, ATM, BCAP31, NKX6-2, GNAO1, WDR73, FA2H, SLC2A1, ATP13A2, YY1 |
| C0020796 | Profound Mental Retardation | 0.25904590 | 3 | (3/139) | 1.863640e-03 | TH, PRKRA, RAB39B | 7.535602e-03 | 5 | (5/139) | 2.832933e-05 | SLC2A1, TH, YY1, PRKRA, PRRT2 |
| C0917816 | Mental deficiency | 0.25904590 | 3 | (3/139) | 1.863640e-03 | TH, PRKRA, RAB39B | 7.535602e-03 | 5 | (5/139) | 2.832933e-05 | SLC2A1, TH, YY1, PRKRA, PRRT2 |
| MP:0001409 | increased stereotypic behavior | 1.00000000 | 2 | (2/51) | 4.437211e-03 | SLC6A3, TH | 1.068880e-02 | 4 | (4/51) | 1.309902e-05 | HTRA2, SLC6A3, TH, TOR1A |
| HP:0003324 | Generalized muscle weakness | 0.75994169 | 3 | (3/118) | 1.251963e-03 | PLA2G6, DCTN1, ATP13A2 | 1.122436e-02 | 5 | (5/118) | 1.448304e-05 | PLA2G6, PNKD, CHMP2B, PRRT2, ATP13A2 |
| HP:0001290 | Generalized hypotonia | 1.00000000 | 6 | (6/933) | 4.938328e-03 | PLA2G6, ATP1A3, SYNJ1, CSF1R, C19ORF12, TH | 1.310906e-02 | 11 | (11/933) | 1.691492e-05 | PLA2G6, ATP1A3, SYNJ1, SGCE, C19ORF12, TOR1A, NKX6-2, GNAO1, HTRA2, SERAC1, TH |
| C1269683 | Major Depressive Disorder | 1.00000000 | 3 | (3/265) | 1.102997e-02 | GCH1, TH, PINK1 | 1.491246e-02 | 6 | (6/265) | 5.606188e-05 | ADCY5, ATP7B, DDC, GCH1, TH, PINK1 |
| MP:0003964 | abnormal noradrenaline level | 0.48130287 | 2 | (2/19) | 6.210360e-04 | SLC6A3, TH | 1.664463e-02 | 3 | (3/19) | 2.039783e-05 | DDC, SLC6A3, TH |
| HP:0001344 | Absent speech | 1.00000000 | 2 | (2/227) | 6.260130e-02 | WDR45, SLC6A3 | 2.114042e-02 | 6 | (6/227) | 2.727796e-05 | GNAO1, WDR45, SERAC1, SLC2A1, SLC6A3, YY1 |
| CRB:XXX | No CRB phenotype | 0.05369845 | 23 | (23/12797) | 1.789948e-03 | ATP13A2, C19orf12, CSF1R, FTL, GBA, GCH1, LYST, PANK2, PARK7, PINK1, PLA2G6, PRKN, PRKRA, PTRHD1, RAB39B, SLC6A3, SLC30A10, SLC39A14, SNCA, SPG11, SPR, SYNJ1, TH | 2.599065e-02 | 32 | (32/12797) | 8.122079e-04 | ADAR, ANO3, APTX, ATM, ATP7B, ATP13A2, C19orf12, CHMP2B, CP, DDC, FA2H, FTL, GCH1, GNAO1, HTRA2, NKX6-2, PANK2, PINK1, PLA2G6, PNKD, PRKN, PRKRA, SERAC1, SGCE, SLC6A3, SLC30A10, SPR, SYNJ1, TH, TOR1A, VAC14, XK |
| MP:0002804 | abnormal motor learning | 1.00000000 | 2 | (2/64) | 6.896078e-03 | MAPT, PARK7 | 2.637289e-02 | 4 | (4/64) | 3.231972e-05 | ATM, DDC, FA2H, SGCE |
| HP:0007002 | Motor axonal neuropathy | 1.00000000 | 1 | (1/25) | 4.445165e-02 | C19ORF12 | 2.986310e-02 | 3 | (3/25) | 3.853303e-05 | C19ORF12, COASY, XK |
| HP:0002131 | Episodic ataxia | 1.00000000 | 1 | (1/26) | 4.618685e-02 | ATP1A3 | 3.369017e-02 | 3 | (3/26) | 4.347119e-05 | ATP1A3, GNAO1, SLC2A1 |
| MP:0002690 | akinesia | 0.90624072 | 2 | (2/26) | 1.169343e-03 | GBA, TH | 4.398621e-02 | 3 | (3/26) | 5.390467e-05 | DDC, HTRA2, TH |